Antioxidants for female subfertility
Information
- DOI:
- https://doi.org/10.1002/14651858.CD007807.pub4Copy DOI
- Database:
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- Cochrane Database of Systematic Reviews
- Version published:
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- 27 August 2020see what's new
- Type:
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- Intervention
- Stage:
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- Review
- Cochrane Editorial Group:
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Cochrane Gynaecology and Fertility Group
- Copyright:
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- Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Cited by:
Authors
Contributions of authors
Marian Showell conducted the searches, assessed studies for inclusion, extracted data, analysed the data and wrote the review.
Rebecca Mackenzie‐Proctor assisted with assessing the trials for inclusion, extracted the data, assisted with the data analysis and helped with the writing of the updated review.
Vanessa Jordan assisted with the methodology in the updated review and commented on the drafts.
Roger Hart helped with the writing of the review and provided clinical advice.
Sources of support
Internal sources
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NZ GOVT MOH, New Zealand
External sources
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None, Other
Declarations of interest
Roger Hart is the Medical Director of Fertility Specialists of WA and a shareholder in Western IVF. He has received educational sponsorship from Merck Serono and Ferring pharmaceuticals, and is on the medical advisory board of MSD and Ferring Pharmaceuticals.
Rebecca Mackenzie‐Proctor: no conflict of interest to declare
Vanessa Jordan: no conflict of interest to declare
Marian Showell: no conflict of interest to declare
Acknowledgements
The authors wish to thank the following people for providing valuable information that assisted in the writing of this review:
Dr Mustafa Nazıroğlu for providing information on the trial Ozkaya 2011;
Aboubakr Elnashar for providing information on the trials Elnashar 2005 and Elnashar 2007;
Dr Rina Agrawal for providing information on the trial Agrawal 2012 and for informing us of her new ongoing trial;
Dr Mohamed Youssef for providing information on the trial Aboulfoutouh 2011 and for informing us that this trial is about to be published;
Dr Badawy for providing information on the trial Badawy 2006;
Dr Lisi for providing information on the trial Lisi 2012;
Dr Battaglia for providing data on the trial Battaglia 2002; and
Dr Eryilmaz for providing information on the trial Eryilmaz 2011
Professor Joanne Barnes
Dr Vahid Seyfoddin for providing translation of the trial Mohammadbeigi 2012
The Cochrane Gynaecology and Fertility Group.
Jane Clarke, who initiated and conceptualised the review, extracted the initial pool of data and wrote the first draft of the review.
Dr Julie Brown assisted with assessing the trials for inclusion, extracted the data, assisted with the data analysis and helped with writing of the original review.
The authors of the 2020 update that Dr Roos Smits, Ms Ann Fonfa and Mrs Anne Lethaby for refereeing the draft.
Version history
| Published | Title | Stage | Authors | Version |
| 2020 Aug 27 | Antioxidants for female subfertility | Review | Marian G Showell, Rebecca Mackenzie-Proctor, Vanessa Jordan, Roger J Hart | |
| 2017 Jul 28 | Antioxidants for female subfertility | Review | Marian G Showell, Rebecca Mackenzie‐Proctor, Vanessa Jordan, Roger J Hart | |
| 2013 Aug 05 | Antioxidants for female subfertility | Review | Marian G Showell, Julie Brown, Jane Clarke, Roger J Hart | |
| 2009 Apr 15 | Antioxidants for female subfertility | Protocol | Jane Clarke, Marian G Showell, Roger J Hart, Ashok Agarwal, Sajal Gupta | |
Differences between protocol and review
After publication of the protocol:
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two of the five protocol authors (Agarwal A, Gupta S) withdrew from involvement in the review.
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we have removed the secondary outcome of stillbirth rate per woman.
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we have removed the exclusion criterion 'Trials that exclusively reported on women who have previously had chemotherapy' as not clinically relevant to this review.
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we have expanded the inclusion criteria for participants to include women undergoing ART. Exclusion criteria now cover trials that enrol exclusively fertile women attending a fertility clinic because of male partner infertility, and women who are Vitamin D‐deficient.
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exclusion criteria for interventions now cover antioxidants versus fertility drugs alone as controls, as they are themselves active agents. They might include metformin or clomiphene citrate.
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the review includes a subgroup analysis based on the type of subfertility problem, including women with PCOS, endometriosis, poor responders and tubal and unexplained subfertility, as well as a subgroup of women who are undergoing IVF or ICSI.
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we have created a separate comparison for pentoxifylline, as we had concerns that this medicine does not have purely antioxidant capabilities.
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we have updated the search strategy.
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we have added two 'Summary of findings' tables.
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where we had data from multi‐armed trials, we have pooled the intervention arms versus the control arm. This differs from the protocol, where we said that we would divide the intervention arms. This was done on the advice of a statistician.
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we decided, with clinical advice, that we would treat trials using folic acid (< 1 mg) as a control as assessing standard treatment, and would include them in the 'no treatment' subgroup.
For the 2017 update:
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we have analysed trials that used an antioxidant plus an antioxidant versus the same antioxidants plus placebo/no treatment or standard treatment in the 'Antioxidants versus no treatment' comparison, whereas in the original review they were considered as head‐to‐head.
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prior to the 2017 update, the effect estimate used was the Peto odds ratio. As this is not recommended as a default approach for meta‐analysis unless intervention effects are small (odds ratios close to one) and events are not particularly common (Higgins 2019), we have used the Mantel‐Haenszel odds ratio for the 2017 update.
For the 2020 update:
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We removed pentoxifylline from the inclusion criteria on clinical advice, as it was deemed to be a medicine rather than an over‐the‐counter supplement, and those formerly included trials were excluded.
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The trials that used inositol for subfertile women with polycystic ovary syndrome were removed, as they are now included in a new Cochrane Review on this topic (Showell 2018).
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We have also expanded the exclusion criterion from only vitamin D‐deficient women to any vitamin deficiency.
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
- Abortion, Spontaneous [epidemiology];
- Administration, Oral;
- Antioxidants [*administration & dosage, adverse effects];
- Infertility, Female [*drug therapy];
- Live Birth [epidemiology];
- Minerals [administration & dosage];
- Oxidative Stress;
- Pentoxifylline [adverse effects, therapeutic use];
- Placebos [administration & dosage];
- Pregnancy Rate;
- Pregnancy, Multiple;
- Randomized Controlled Trials as Topic;
- Vitamins [administration & dosage];
Medical Subject Headings Check Words
Female; Humans; Pregnancy;
PICOs
Methodological risk of bias summary: review authors' judgements about each methodological bias item for each included study.
Methodological risk of bias graph: review authors' judgements about each methodological bias item presented as percentages across all included trials.
Funnel plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.5 Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.1 Live birth; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.5 Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.9 Adverse events.
Forest plot of comparison: 2 Head‐to‐head antioxidants, outcome: 2.1 Live birth; type of antioxidant (natural conceptions and undergoing fertility treatments).
Forest plot of comparison: 2 Head‐to‐head antioxidants, outcome: 2.4 Clinical pregnancy; type of antioxidant (natural conceptions and undergoing fertility treatments).
Forest plot of comparison: 2 Head‐to‐head antioxidants, outcome: 2.7 Adverse events.
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 1: Live birth; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 2: Live birth; type of antioxidant
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 3: Live birth; indications for subfertility
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 4: Live birth; IVF/ICSI
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 5: Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 6: Clinical pregnancy; type of antioxidant
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 7: Clinical pregnancy; indications for subfertility
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 8: Clinical pregnancy; IVF/ICSI
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 9: Adverse events
Comparison 2: Head‐to‐head antioxidants, Outcome 1: Live birth; type of antioxidant (natural conceptions and undergoing fertility treatments)
Comparison 2: Head‐to‐head antioxidants, Outcome 2: Live Birth; indications for subfertility
Comparison 2: Head‐to‐head antioxidants, Outcome 3: Live Birth; IVF/ICSI
Comparison 2: Head‐to‐head antioxidants, Outcome 4: Clinical pregnancy; type of antioxidant (natural conceptions and undergoing fertility treatments)
Comparison 2: Head‐to‐head antioxidants, Outcome 5: Clinical pregnancy; indications for subfertility
Comparison 2: Head‐to‐head antioxidants, Outcome 6: Clinical pregnancy; IVF/ICSI
Comparison 2: Head‐to‐head antioxidants, Outcome 7: Adverse events
| Antioxidant(s) compared to placebo or no treatment/standard treatment for female subfertility | ||||||
| Patient or population: women with subfertility | ||||||
| Outcomes | Relative effect | Anticipated absolute effects* (95% CI) | Quality of the evidence | What happens | ||
|---|---|---|---|---|---|---|
| Without antioxidant(s) | With antioxidant(s) | Difference | ||||
| Live birth; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments) | OR 1.81 | 19.0% | 29.8% | 10.8% more | ⊕⊝⊝⊝ | We are uncertain whether antioxidants improve live birth rate compared with placebo or no treatment/standard treatment. |
| Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments) | OR 1.65 | 18.8% | 27.6% | 8.8% more | ⊕⊕⊝⊝ | Antioxidant(s) may improve clinical pregnancy rate, compared with placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments). |
| Adverse events ‐ Miscarriage | OR 1.13 | 4.8% | 5.4% | 0.6% more | ⊕⊕⊝⊝ | Antioxidant(s) may result in little to no difference in adverse events ‐ Miscarriage |
| Adverse events ‐ Multiple pregnancy | OR 1.00 | 4.3% | 4.3% | 0.0% fewer | ⊕⊕⊝⊝ | Antioxidant(s) may result in little to no difference in adverse events ‐ Multiple pregnancy |
| Adverse events ‐ Gastrointestinal disturbances | OR 1.55 | 2.4% | 3.7% | 1.3% more | ⊕⊕⊝⊝ | Antioxidant(s) may result in little to no difference in adverse events ‐ Gastrointestinal disturbances |
| Adverse events ‐ Ectopic pregnancy | OR 1.40 | 0.6% | 0.9% | 0.3% more | ⊕⊕⊝⊝ | Antioxidant(s) may result in little to no difference in adverse events ‐ Ectopic pregnancy |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to serious risk of bias. The no‐treatment group increases risk due to the lack of blinding. | ||||||
| Head‐to‐head antioxidants for female subfertility | ||||||
| Patient or population: women with subfertility | ||||||
| Outcomes | Relative effect | Anticipated absolute effects* (95% CI) | Quality of the evidence | What happens | ||
|---|---|---|---|---|---|---|
| With one antioxidant | With another antioxidant | Difference | ||||
| Live birth; type of antioxidant (natural conceptions and undergoing fertility treatments) ‐ Melatonin lower dose versus melatonin higher dose | OR 0.94 | 24.0% | 22.9% | 1.1% fewer | ⊕⊕⊝⊝ | There was no clear evidence of a difference between the lower and higher doses of melatonin |
| Clinical pregnancy; type of antioxidant (natural conceptions and undergoing fertility treatments) ‐ N‐acetylcysteine versus L‐carnitine | OR 0.81 | 14.6% | 12.2% | 2.4% fewer | ⊕⊝⊝⊝ | There was no clear evidence of a difference between N‐acetylcysteine versus L‐carnitine |
| Clinical pregnancy; type of antioxidant (natural conceptions and undergoing fertility treatments) ‐ Melatonin lower dose versus melatonin higher dose | OR 0.94 | 24.0% | 22.9% | 1.1% fewer | ⊕⊕⊝⊝ | There was no clear evidence of a difference between the lower and higher doses of melatonin |
| Adverse events ‐ Miscarriage | OR 1.54 (0.42 to 5.67) | 3.0% | 4.6% (1.3 to 15.1) | 1.6 more (1.7 fewer to 12.1 more) | ⊕⊕⊝⊝ | There were no miscarriages in either melatonin study (140 women) There was no clear evidence of a difference between N‐acetylcysteine versus L‐carnitine (164 women) |
| Adverse events ‐ Multiple pregnancy | There were no trials reporting multiple pregnancy | |||||
| Adverse events ‐ Gastrointestinal disturbances | There were no trials reporting gastrointestinal disturbances | |||||
| Adverse events ‐ Ectopic pregnancy Melatonin lower dose versus melatonin higher dose | Not estimable, there were no ectopic pregnancies in either group | ⊕⊝⊝⊝ | There was no clear evidence of a difference between the lower and higher doses of melatonin | |||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level as there are only two trials in this analysis and one is small. | ||||||
| Outcome | Data | Notes |
|---|---|---|
| Clinical pregnancy rate; myo‐inositol + folic acid | 4/23 | Only 42 of the 92 women enrolled in this trial declared a desire to become pregnant |
| Clinical pregnancy rate; folic acid + placebo | 1/19 | ‐ |
| Miscarriage rate; myo‐inositol + folic acid | Miscarriage reported, but unknown whether from treatment or control | 1 miscarriage occurred in the first trimester, but it is unknown from which group |
| Miscarriage rate; folic acid + placebo | Unknown | ‐ |
| Trial | Pregnancy in antioxidant group | Pregnancy in control group |
|---|---|---|
| 0/16 (vitamins C + E), at follow‐up over 9 months 3/16 | 0/18 (placebo), at follow‐up over 9 months 2/18 | |
| 9/22 (vitamin D) | 7/22 (placebo) | |
| 6/32 (selenium) | 1/32 (placebo) | |
| 20/60 (omega) | 15/58 (placebo) | |
| 7/33 (NAC + CC) | 5/33 (CC) | |
| 6/20 (selenium) | 5/20 (placebo) | |
| 5/20 (chromium) | 4/20 (placebo) | |
| 0/6 (myo‐inositol + 200 µg folic acid twice a day) | 0/6 (400 µg folic acid once a day) | |
| CC: clomiphene citrate; NAC: N‐acetylcysteine | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Live birth; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments) Show forest plot | 13 | 1227 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.81 [1.36, 2.43] |
| 1.1.1 Placebo | 7 | 628 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.89 [1.18, 3.03] |
| 1.1.2 No treatment | 6 | 599 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.77 [1.22, 2.56] |
| 1.2 Live birth; type of antioxidant Show forest plot | 13 | 1227 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.81 [1.36, 2.43] |
| 1.2.1 N‐acetyl‐cysteine | 1 | 60 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.00 [1.05, 8.60] |
| 1.2.2 L‐arginine | 1 | 37 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.43 [0.09, 2.09] |
| 1.2.3 CoQ10 | 2 | 225 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.50 [0.78, 2.88] |
| 1.2.4 Vitamin D | 1 | 52 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.21, 3.02] |
| 1.2.5 Vitamin B complex | 1 | 102 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.07 [0.93, 4.57] |
| 1.2.6 Combined antioxidants | 3 | 378 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.59 [1.52, 4.40] |
| 1.2.7 Vitamin E | 1 | 103 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.50, 4.10] |
| 1.2.8 Melatonin | 3 | 270 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.60 [0.68, 3.76] |
| 1.3 Live birth; indications for subfertility Show forest plot | 11 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 Polycystic ovary syndrome | 3 | 362 | Odds Ratio (M‐H, Fixed, 95% CI) | 3.34 [1.90, 5.86] |
| 1.3.2 Tubal subfertility | 1 | 37 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.43 [0.09, 2.09] |
| 1.3.3 Varying indications | 3 | 338 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.70 [1.02, 2.83] |
| 1.3.4 Unexplained subfertility | 2 | 133 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.50 [0.60, 3.72] |
| 1.3.5 Poor ovarian reserve | 2 | 266 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.75 [0.83, 3.67] |
| 1.4 Live birth; IVF/ICSI Show forest plot | 9 | 806 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.36 [0.96, 1.93] |
| 1.5 Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments) Show forest plot | 35 | 5165 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.65 [1.43, 1.89] |
| 1.5.1 Placebo | 17 | 3292 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.70 [1.42, 2.05] |
| 1.5.2 No treatment/standard treatment | 19 | 1873 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.57 [1.28, 1.94] |
| 1.6 Clinical pregnancy; type of antioxidant Show forest plot | 35 | 5165 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.65 [1.43, 1.89] |
| 1.6.1 N‐acetylcysteine | 8 | 1590 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.36 [1.05, 1.77] |
| 1.6.2 Combined antioxidants | 5 | 689 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.90 [1.33, 2.70] |
| 1.6.3 Melatonin | 7 | 678 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.66 [1.12, 2.47] |
| 1.6.4 Vitamin E | 1 | 103 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.43 [0.50, 4.10] |
| 1.6.5 Ascorbic acid | 2 | 899 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.66, 1.25] |
| 1.6.6 L‐arginine | 2 | 71 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.32, 3.46] |
| 1.6.7 Myo‐inositol plus folic acid | 1 | 94 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.24 [0.50, 3.06] |
| 1.6.8 CoQ10 | 4 | 397 | Odds Ratio (M‐H, Fixed, 95% CI) | 2.49 [1.50, 4.13] |
| 1.6.9 L‐carnitine | 2 | 450 | Odds Ratio (M‐H, Fixed, 95% CI) | 11.14 [5.70, 21.81] |
| 1.6.10 Vitamin D | 2 | 92 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.25, 2.76] |
| 1.6.11 Vitamin B complex | 1 | 102 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.94 [0.82, 4.58] |
| 1.7 Clinical pregnancy; indications for subfertility Show forest plot | 31 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.7.1 Polycystic ovary syndrome | 15 | 1908 | Odds Ratio (M‐H, Fixed, 95% CI) | 4.24 [3.23, 5.56] |
| 1.7.2 Unexplained | 4 | 997 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.61, 1.16] |
| 1.7.3 Tubal subfertility | 2 | 71 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.32, 3.46] |
| 1.7.4 Varying indications | 6 | 1135 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.85, 1.52] |
| 1.7.5 Poor responders | 1 | 65 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.88 [0.64, 5.47] |
| 1.7.6 Poor ovarian reserve | 2 | 266 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.70 [0.86, 3.37] |
| 1.7.7 Endometriosis | 1 | 280 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.19 [0.71, 1.98] |
| 1.8 Clinical pregnancy; IVF/ICSI Show forest plot | 18 | 2341 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.95, 1.40] |
| 1.9 Adverse events Show forest plot | 27 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.9.1 Miscarriage | 24 | 3229 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.82, 1.55] |
| 1.9.2 Multiple pregnancy | 9 | 1886 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.63, 1.56] |
| 1.9.3 Gastrointestinal disturbances | 3 | 343 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.55 [0.47, 5.10] |
| 1.9.4 Ectopic pregnancy | 4 | 404 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.40 [0.27, 7.20] |
| 1.9.5 Headache | 2 | 330 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.45, 1.75] |
| 1.9.6 Congenital (missing kidney) | 1 | 160 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.04, 25.46] |
| 1.9.7 Low birth weight < 2.500 g | 1 | 160 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.11 [0.00, 2.74] |
| 1.9.8 Preterm birth | 2 | 220 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.31 [0.17, 9.93] |
| 1.9.9 Placenta praevia | 1 | 160 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.02 [0.04, 25.46] |
| 1.9.10 Pre‐eclampsia | 1 | 160 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.71 [0.08, 36.35] |
| 1.9.11 Fatigue | 1 | 160 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.86 [0.75, 4.62] |
| 1.9.12 Ovarian hyperstimulation syndrome (OHSS) | 1 | 150 | Odds Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Live birth; type of antioxidant (natural conceptions and undergoing fertility treatments) Show forest plot | 2 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.41, 2.15] |
| 2.1.1 Melatonin lower dose versus melatonin higher dose | 2 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.41, 2.15] |
| 2.2 Live Birth; indications for subfertility Show forest plot | 2 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.2.1 Unexplained subfertility | 1 | 20 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.15, 6.77] |
| 2.2.2 Varying Indications | 1 | 120 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.37, 2.32] |
| 2.3 Live Birth; IVF/ICSI Show forest plot | 2 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.41, 2.15] |
| 2.4 Clinical pregnancy; type of antioxidant (natural conceptions and undergoing fertility treatments) Show forest plot | 3 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.4.1 N‐acetylcysteine versus L‐carnitine | 1 | 164 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.33, 2.00] |
| 2.4.2 Melatonin lower dose versus melatonin higher dose | 2 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.41, 2.15] |
| 2.5 Clinical pregnancy; indications for subfertility Show forest plot | 3 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.5.1 Polycystic ovary syndrome | 1 | 164 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.81 [0.33, 2.00] |
| 2.5.2 Unexplained subfertility | 1 | 20 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.15, 6.77] |
| 2.5.3 Varying indications | 1 | 120 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.37, 2.32] |
| 2.6 Clinical pregnancy; IVF/ICSI Show forest plot | 2 | 140 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.41, 2.15] |
| 2.7 Adverse events Show forest plot | 3 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.7.1 Miscarriage | 3 | 304 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.54 [0.42, 5.67] |
| 2.7.2 Ectopic pregnancy | 1 | 120 | Odds Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 2.7.3 Congenital (missing kidney) | 1 | 120 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.53 [0.06, 38.36] |
| 2.7.4 Low birth weight < 2.500 g | 1 | 120 | Odds Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 2.7.5 Birth between 34 and 37 weeks | 1 | 120 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.03, 8.10] |
| 2.7.6 Placenta praevia | 1 | 120 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.53 [0.06, 38.36] |
| 2.7.7 Pre‐eclampsia | 1 | 120 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.49 [0.03, 8.10] |
